EARLY ANTIBODY THERAPY CAN INDUCE SUSTAINED CELLULAR IMMUNITY TO SHIV INFECTIONS OF MACAQUES. Highly potent and broadly neutralizing anti-HIV-1 antibodies (bNAbs) have recently been used to prevent and treat lentivirus infections in humanized mice, macaques and humans. We previously reported that the administration of a single 2-week course of two potent bNAbs (3BNC117 and 10-1074) 3 days following SHIVAD8-EO inoculation by mucosal or intravenous routes of rhesus macaques led to long-term control of virus replication in 6 of 13 animals; plasma virus loads declined to undetectable levels in these 6 elite controller macaques between 1 and 2 years following the onset of virus infection. Infusion of a T cell depleting anti-CD8 mAb into the controller monkeys led to the specific and transient decline in levels of CD8+ T cells and rapid reappearance of plasma viremia. This wave of virus replication was subsequently suppressed with the re-emergence of CD8+ T cells. Plasma viremia has remained at low/undetectable levels in the elite controllers for nearly 4 years. We have discovered that a unique virus-specific CXCR5+ CD8+ T cell subset accumulates and is maintained in the lymph nodes (LNs), but not in the circulation, of the controller monkeys. In other chronic virus-infected animal systems, CXCR5+ CD8+ T cells have been shown to migrate into B-cell follicles, to express lower levels of inhibitory receptors and to exhibit more potent cytotoxicity than the CXCR5 minus CD8+ T cell subset. Similar results were obtained in an independent replicate experiment in which bNAb administration starting at day 3 post infection conferred elite controller status in 7 of 12 monkeys. We conclude that passive bNAb immunotherapy during the acute SHIV infection differs from cART by facilitating the emergence of potent CD8+ T cell immunity able to durably suppress virus replication. We have recently extended the sustained control of SHIV infections mediated by early immunotherapy to a more clinically relevant time by beginning bNAb treatments at 2 weeks rather than 3 days following virus challenge. Whether administered alone, or in combination with anti-retroviral drugs, bNAb intervention at week 2 post infection (PI) has resulted in control of plasma viremia to undetectable levels in 9 of 18 animals within 1 to 2 years of treatment initiation. In this ongoing study, LN specimens are being evaluated for the presence of the CXCR5+ CD8+ T cell subset and depleting anti-CD8+ T cell mAbs will be infused into the treated monkeys to verify the role of this T cell subset in conferring controller status. THE DESIGN AND USE OF A PRIMING IMMUNOGEN TO ELICIT NEUTRALIZING V3-GLYCAN ANTIBODIES. The development of an effective anti-HIV-1 vaccine has proven to be elusive despite massive effort over the past 30 years. Numerous recent studies suggest that vaccination to elicit bNAbs requires a series of sequential immunogens starting with an immunogen that induces the expansion of B lymphocytes that carry germline precursors (IGPs)of bNAbs. Because native-like HIV envelope immunogens fail to bind to these IGPs, newly designed immunogens have been designed to recruit B-cells expressing bNAb precursors in humanized mouse systems. In collaboration with Drs. Michel Nussenzweig (Rockefeller University) and Pamela Bjorkman (California Institute of Technology), we have recently reported the design and use of an engineered HIV-1 envelope derivatives thjat can induce the expansion of B lymphocytes expressing appropriate germline precursors of bNAbs in vaccinated monkeys. This immunogen, designated RC1, facilitates recognition of the V3-glycan patch on HIV-1 Env while concealing non-conserved immunodominant regions by addition of glycans and/or multimerization on virus-like particles. Antibody cloning and cryo-EM structures of antibody-Env complexes confirmed that RC1 immunization expands clones of B-cells carrying anti-V3-glycanpatch antibodies that resemble predicted precursors of human bNAbs. Thus, RC1 is a suitable priming immunogen for vaccination strategies to elicit V3-glycan antibodies in the context of polyclonal repertoires.